Fertiprotekt, Oncofertility Consortium and the Danish Fertility

FertiPROTEKT, Oncofertility Consortium and the Danish Fertility-Preservation Networks What Can We Learn From Their Experiences? von Wolff, Michael; Andersen, Claus Yding; Woodruff, Teresa K; Nawroth, Frank

Published in: Clinical Medicine Insights: Reproductive Health

DOI: 10.1177/1179558119845865

Publication date: 2019

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Citation for published version (APA): von Wolff, M., Andersen, C. Y., Woodruff, T. K., & Nawroth, F. (2019). FertiPROTEKT, Oncofertility Consortium and the Danish Fertility-Preservation Networks: What Can We Learn From Their Experiences? Clinical Medicine Insights: Reproductive Health, 13, 1-17. https://doi.org/10.1177/1179558119845865

Download date: 29. sep.. 2021 REH0010.1177/1179558119845865Clinical Medicine Insights: Case ReportsWolff et al 845865review-article2019

Clinical Medicine Insights: Reproductive Health FertiPROTEKT, Oncofertility Consortium and the Volume 13: 1–17 © The Author(s) 2019 Danish Fertility-Preservation Networks – What Can Article reuse guidelines: sagepub.com/journals-permissions We Learn From Their Experiences? DOI:https://doi.org/10.1177/1179558119845865 10.1177/1179558119845865 Michael von Wolff1 , Claus Yding Andersen2, Teresa K Woodruff3 and Frank Nawroth4 1University Women’s Hospital, Division of Gynaecological Endocrinology and Reproductive Medicine, Inselspital, University Hospital, Bern, Switzerland. 2Laboratory of Reproductive Biology, Faculty of Health Science, The Juliane Marie Centre for Women, Children and Reproduction, University Hospital of Copenhagen, University of Copenhagen, Copenhagen, Denmark. 3Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL, USA. 4Centre for Infertility, Prenatal Medicine, Endocrinology and Osteology, Amedes group, Hamburg, Germany.

ABSTRACT: Fertility preservation is an increasingly important discipline. It requires close coordination between reproductive medicine specialists, reproductive biologists, and oncologists in various disciplines. In addition, it represents a particular health policy challenge, since fertility-protection measures are to be understood as a treatment for side effects of gonadotoxic treatments and would therefore normally have to be reimbursed by health insurance companies. Therefore, it is inevitable that fertility-preservation activities should organise themselves into a network structure both as a medical-logistic network and as a professional medical society. The necessary network structures can differ significantly at regional, national, and international level, as the size of the regions to be integrated and the local cultural and geographical conditions, as well as the political conditions are very different. To address these issues, the current review aims to point out the basic importance and the chances but also the difficulties of fertility-protection networks and give practical guidance for the development of such network structures. We will not only discuss network structures theoretically but also present them based on three established, different sized networks, such as the Danish Network (www.rigshospitalet.dk), representing a centralised network in a small country; the German-Austrian-Swiss network FertiPROTEKT® (www.fertiprotekt.com), representing a centralised as well as decentralised network in a large country; and the Oncofertility® Consortium (www.oncofertility.northwestern.edu), representing a decentralised, internationally oriented network, primarily serving the transfer of knowledge among its members.

Keywords: fertility preservation, network, FertiPROTEKT, Oncofertility Consortium, ovarian tissue, transplantation

RECEIVED: January 12, 2019. ACCEPTED: February 27, 2019. Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this Type: Review article.

Funding: The author(s) received no financial support for the research, authorship, and/or CORRESPONDING AUTHOR: Michael von Wolff, University Women’s Hospital, Division publication of this article. of Gynaecological Endocrinology and Reproductive Medicine, Inselspital, University Hospital, Friedbühlstrasse 19, 3010 Bern, Switzerland. Email: [email protected]

Introduction reimbursed by health insurance companies, which is not yet Since the birth of the first child after ovarian tissue transplan- the case in many countries. tation, fertility protection in women and men has developed Due to these special features of this field, it is inevitable that into a new and clinically relevant independent field.1 This field all the scientific, clinical, and, if necessary, even health care has a number of special features. policy areas involved organise themselves into a network struc- On one hand, the discipline is interdisciplinary, since fertil- ture both as a medical-logistic network and as a professional ity protection requires close coordination between reproductive medical society. medicine specialists, reproductive biologists, and oncologists in The necessary network structures can differ significantly at various disciplines. regional, national, and international level, as the size of the On the other hand, some fertility-preserving measures such regions to be integrated and the local cultural and geographical as transplantation of ovarian tissue, in vitro maturation of conditions, as well as the political conditions are very different. oocytes, maturation of oocytes from ovarian tissue, and the Therefore, in this article, we would like to point the basic cryopreservation of testicular tissue from prepubertal boys are importance and the chances, but also the difficulties, of fertil- still in clinical or even scientific development and therefore ity-protection networks and give practical guidance for the require a high degree of specialisation on the part of the centres development of such network structures. We will not only dis- involved.2-5 cuss network structures theoretically but also present them In addition, this new specialist field represents a particular based on three established different sized networks. These health policy challenge, since fertility-protection measures three networks have different goals and different logistic struc- are to be understood as a treatment for side effects of gonado- tures and thus cover the possible range of possible network toxic treatments and would therefore normally have to be structures.

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The selected networks are as follows:

1. The Danish Network (www.rigshospitalet.dk). This network is a centralised network for the practical implementation of specific fertility-preserving techniques such as the cryopreservation and transplantation of ovarian tissue in a small country. 2. The German-Austrian-Swiss network FertiPROTEKT (www.fertiprotekt.com). This network is a centralised as well as decentralised network that controls the implementation of fertility-protective techniques in a large country. 3. The Oncofertility Consortium (www.oncofertility. Figure 1. Networks are frequently set up as multimodular structures. northwestern.edu). This is a decentralised, internation- Small modules (blue) such as infertility centres or hospitals integrate ally oriented network that primarily serves the transfer gynaecologists and oncologists etc. (green). Several of these small modules (blue) are organised as a medium-sized network (orange) such of knowledge among its members. as regional or small national networks. Several of these medium-sized modules (orange) are organised as a large network with a centralised Network Structure body (red) which organises registries, scientific activities, conferences, The structure of a network depends on the following mostly and so on. given and therefore unchangeable conditions and the self- imposed goals: The establishment of a good regional or national network should try to achieve all these goals. Only partial implementa- Given conditions for the establishment of a network tion is possible in some regions and countries.

Size of the region to be networked. Structural composition of networks Transport-logistical development of the region. Networks are often modular; the number of modules depends Density and area coverage of reproductive medicine cen- on their size (Figure 1). tres. The conditions and intentions of these modules are differ- Willingness of the centres and doctors to cooperate ent (Table 1). The smallest modular unit is usually a reproductive medicine centre or a clinic that networks regionally or Political and financial support. within the clinic with oncologists. Patients are referred to the Health care policy conditions. reproductive medicine centres directly by the oncologists. The therapy decision is often based on direct bilateral communica- These conditions are largely unchangeable. Accordingly, the tion. The reproductive medicine centre documents the treat- desired network structures must take these conditions into ments so that the data can later be passed on to a registry. account and integrate them into the network concepts. The next medium-sized modular stage is a union of local units into a small national or large regional network. An example of such a network is Denmark (www.rigshospitalet.dk). Goals for the establishment of a network The centres know each other, and personal communication is possible. Data from the local units are merged into a register, A nationwide supply with specialised centres should be which is relatively easy to create due to its limited size. It is eas- established. ily possible to establish centralised, highly specialised facilities, Individual, especially not yet fully established or experi- for example, cryopreservation of gonadal tissue. The establish- mental reproductive techniques such as cryopreservation ment of such centralised facilities allows high-quality fertility- and transplantation of ovarian tissue and cryopreserva- protective techniques, scientific evaluation, good transparency tion of testicular tissue from prepubertal boys should be of activities, and thus also health care policy initiatives. Due to centralised. short travel distances, shorter training courses can be organised with the help of oncologists. The strengths of these medium- Regular information events should be carried out by the sized networks lie in the possibility of being able to collect participating centres and associated disciplines. high-quality data, as detailed data documentation is usually A data register is to be established. possible. Wolff et al 3

Table 1. Characteristics of the different sized networks.

Characteristics Local and Small national Large national Very large regional or nationwide networks networks or networks networks continental networks

Example Reproductive Danish network FertiPROTEKT Oncofertility Consortium medicine centre or (www.rigshospitalet.dk) (www.fertiprotekt.com) (www.oncofertility. clinic northwestern.edu)

Centralization of Yes Yes, mostly one facility Yes, mostly several facilities Rather no facilities (eg storage of gonadal tissue)

Continuing education Bilateral exchange Continuing education National congresses International congresses

Data collection in Very possible Quite possible, high data Possible, lower data quality, Possible to a limited registers quality but high data quantity extent

Political activities Not as good Good Good Not as good

In very large regions or larger countries, several network When setting up a network, priority should be given to structures are combined into one large network. One such examining what can motivate active participation. University example is the FertiPROTEKT network (www.fertiprotekt. centres are often more interested in scientific activities and com). Accordingly, there may be several central cryopreser- cooperation, private centres more in economic advantages, and vation facilities. Continuing education takes place every 1 to the use of networks as an advertising platform. Possible moti- 2 years, mainly with reproductive physicians and biologists, vations for active participation must be identified and inte- but less with oncologists. These are usually spread over 1 to grated into the network programmes. The willingness to 2 days because of the longer travelling distances. A register participate in the network can often be increased by a demo- requires good and easy-to-use online input tools to ensure cratic voice. If there is a danger that the right to have a say in reliable data entry. The strength of these large networks lies the network will hamper its development, a democratically in their ability to collect relevant amounts of data. The level elected network board can also make sense to promote the of detail of this data is limited by online data collection. development and expansion in a targeted manner with a small In addition, it is possible to combine several of these net- group of board members. works for data collection and professional exchange. Examples of such international networks are the ‘Oncofertility® Financing of Networks Consortium’ (www.oncofertility.northwestern.edu), the Special The financing of networks differs regionally and nationally. Interest Group ‘Fertility Preservation’ of the European Society The start-up financing for setting up a network may differ. of Human Reproduction and Embryology (ESHRE) (www. Only a few thousand Euros were initially available from a eshre.eu/Specialty-groups/Special-Interest-Groups/Fertility- pharmaceutical company for the FertiPROTEKT network to Preservation.aspx), and the ‘International Society for Fertility set up a website. All other costs were covered by the members. Preservation’ (ISFP) (www.isfp-fertility.org). Annual continuing education was covered by pharmaceutical companies and participation fees. All other activities were ini- Obstacles to Creating Networks tially performed voluntarily. The explanations have shown that networks are clinically, sci- In contrast, the United States initially made 22 million entifically, and politically of great importance. In practice, how- dollars available for the founding of the Oncofertility ever, they are often difficult to implement. Consortium. What are the reasons for this? Undoubtedly, generous start-up financing is advantageous In most cases, networks can only be implemented in regions for the establishment of a network. Far more decisive is not the and countries that have good medical, technical, and infra- amount of funding but the initiative and willingness of a few structure care. Thus, the topic of fertility protection can only be people. of importance if sufficient oncological care is guaranteed. If The following are necessary to start a network: these requirements are not met, network-based care with fertil- •• ity-protective measures is hardly possible. An initiation meeting with as many reproductive medi- In industrialised, well-developed countries, there are no cine centres as possible. •• infrastructural obstacles to the establishment of networks. The development of a network name and logo. •• Nevertheless, it is often difficult to build networks. The main A website that can be created largely free of charge by obstacle is the ‘human factor’ (Table 2). network members with IT experience. 4 Clinical Medicine Insights: Reproductive Health

Table 2. The human factor as the main obstacle in the establishment of networks.

Obstacles to Ways to avoid these obstacles establishing networks

Scientific competition • Consideration of all persons involved as co-authors in publications Lack of time for documentation • High-quality documentation software • Interfaces with already established national registers to avoid repeated entries Lack of interest • Sensitisation to the fact that fertility-protective measures are also economically relevant • Use of the network website as an advertising platform for member centres • Democratic voice in decision-making processes • Annual membership meetings at interesting locations with an interesting programme • Introduction of certificates for member centres and their external presentation Lack of awareness • Development of good websites and linking to member centres to increase Internet presence • Regional and national information events Lack of willingness to cooperate • Development of political activities to enforce cooperation

•• An online documentation tool which can be created hospital in 1999, and soon thereafter, other parts of Denmark largely free of charge by network members with IT also wanted to start. We shortly realised that it would be more experience. effective if we could centralise this service, which at that time •• Regular (eg annual) continuing education events. was only performed occasionally. Instead of doing few cases per centre, we reasoned that it would provide a better service if the Introduction of the Danish Network – Centralised activity was centralised to the laboratory in which the knowl- Network for Smaller Countries/Large Cities edge and expertise of dealing the human ovaries was already History available. On this background, we developed what is now known as the Danish concept for freezing ovarian tissue ‘the Inspired by research efforts three decades ago from a large woman stays the tissue moves’ (Figures 2 and 3).9-12 number of people including Roger Gosden, Outi Hovatta, Kutluk Oktay, and David Baird, it became clear that it would be potentially clinically feasible to freeze human ovarian tissue Structure with the intention of replacing it later to restore ovarian func- Cancer treatment in Denmark is centralised mainly to three tion. At the end of the last century, encouraging results emerged university hospitals located in different parts of Denmark. from primate studies and from transplantation of human ovar- Each of these hospitals also has a fertility clinic which focus on ian tissue.6,7 This sparked the first clinical initiatives of freezing in vitro fertilisation (IVF) treatment and other assisted repro- ovarian tissue in the United Kingdom and Belgium. In ductive technology (ART) procedures. In addition, our net- Denmark, our laboratory conducted a number of mouse stud- work now also includes Skåne Region of Sweden, in which the ies, in which different cryoprotectants and freezing protocols University Hospital of Lund and Malmø are members. These were evaluated.8 However, Danish legislation clearly stated two regions have entered a formal agreement, allowing patients that it was illegal to transplant ovarian tissue to a woman. In from one country to be treated in other country in the area of 1998, we had a direct correspondence with Danish Minister of reproductive medicine. The Swedish side also has a fertility Health and he concluded that there were no restrictions on clinic that is coordinating the local counselling. The Skåne freezing ovarian tissue from a woman as long as only autolo- Region is now connected to Copenhagen via a bridge, and the gous transplantation was considered. There was no time limit transport time from the local hospital to the central laboratory on the storage period and normal medical rules applied for use is maximally 1 to 2 hours by car and lower from other parts of of this technique including replacement of frozen thawed tis- Denmark. Importantly, all these clinics are public-funded hos- sue. In addition, the Minister of Health informed that similar pitals, and patients receive treatment for free paid for by the rules applied for testicular tissue. This was basically a very lib- taxes, including extraction of tissue, freezing, storage, and eral rule that placed this new technique in the context of nor- transplantation. Furthermore, if ART is needed after trans- mal medical practice and the concept of ‘do no harm’. plantation, this will also be covered by the public health care At the end of the last century, our own laboratory had a system. Basically, any Danish woman or women in the Skåne more than 40-year-old tradition for studying the physiology of Region of Sweden, who potentially may benefit from these and working with human ovaries as the only laboratory in procedures and who qualify for these treatments (ie age, diag- Denmark focussing on female reproduction. We started out nosis, and clinical evaluation) should have it offered and then it with a clinical service freezing ovarian tissue at our local is her decision to accept or decline the offer. Wolff et al 5

Figure 2. Number of cryopreservations of ovarian tissue per year in the collaborating centres covering all of Denmark and the very southern part of Sweden.

Figure 3. Yearly number of cryopreservations of ovarian tissue (grey bar) and number of transplantations of frozen/thawed ovarian tissue (black bar).

In each of these fertility clinics, one or two consultants have After cryopreservation, the tissue will be stored at the cen- specialised in fertility preservation. Patients potentially requiring tral laboratory and kept in liquid nitrogen until potential use or fertility preservation identified in the oncological, haematologi- until the patient decides otherwise for her tissue. The central cal, or other departments in which patients are exposed to poten- laboratory is accredited by the Danish authorities to conduct tial gonadotoxic treatment are referred to the consultants of the this treatment including a licence according to the European fertility clinic where they immediately get a consultation. Here, Union (EU) tissue directive. We have collaborated with the the different options are discussed with the patient including competent Danish authorities to formulate guidelines for new ovarian stimulation with cryopreservation of mature oocytes, clinics and networks starting out to cryopreserved ovarian tis- excision, and cryopreservation of ovarian tissue or doing nothing. sue.13 If the patient request transplantation, the tissue will be Depending on the clinical evaluation and the patient’s wishes, a transported in liquid nitrogen to the local hospital, where the plan for fertility preservation is agreed upon. In case freezing of surgical procedure of replacing the tissue will take place. ovarian tissue is planned, a date will be agreed upon with the The clinical follow-up of transplanted patients is performed central laboratory performing the cryopreservation and the sur- by the local hospital including monitoring of whether the geons excising the ovarian tissue at the local hospital. patient becomes pregnant, experience relapse and so on. The surgical intervention to extract the tissue is normally Representatives from the participating clinics in the net- the first operation on that day, and the tissue will be able to work will meet to discuss the service and results to align poli- reach the central laboratory in maximally 4 to 5 hours. After cies and various other matters when needed. We are setting up excision of the ovarian tissue, the surgeon will bring it to the a framework for a database containing all information on local laboratory, where the tissue is placed in a 50-ml tube with patients who have ovarian tissue cryopreserved, which will pro- basal medium that goes into a flamingo-box filled with crushed vide valuable information looking forward. The competent ice to maintain temperatures around 0°C. The box is trans- Danish authorities secure implementation of the EU tissue ported to the central laboratory that checks for the presence of directive and also function as advisers to the political system. ice and processes the tissue immediately after arrival. We have discussions with authorities and have direct political 6 Clinical Medicine Insights: Reproductive Health

Table 3. Scientific focus and examples of corresponding contacts where we try to modify the Danish regulations to publications with the participation of the Danish network. allow storage of tissue for social indications and for postponing menopause at the cost of the patient herself. Scientific focus Examples of publications

New technologies, •• Andersen et al14 • 15 Financial support options, and issues of •• Schmidt et al importance for fertility •• Rosendahl et al16 preservation and •• Rosendahl et al17 Initially, the project was financed from external funding by the 18 restoration •• Schmidt et al Danish Cancer Society, but around the last 10 years, the treat- •• Andersen et al19 20 ment has been recognised as an established treatment that the •• Donnez et al •• Andersen21 public health care system covers. As the technique is almost •• Andersen and Kristensen22 exclusively performed in the public system of hospitals that •• Kristensen et al23 •• Andersen et al13 accounts for more than 99% of activity in the medical field •• Kristensen et al24 anyway, the patient categories who have this technique offered •• Andersen and Byskov25 • Human small antral for free have been limited to patients with a risk of iatrogenic- follicles •• Andersen et al26 •• Nielsen et al27 induced follicle loss and infertility plus patients with a genetic •• Andersen et al28 condition that may render them infertile prematurely. •• Nielsen et al29 •• Jeppesen et al30 •• Jeppesen et al31 Scientific focus •• Jeppesen et al32 •• Kristensen et al24 The scientific focus in Denmark has during recent years been In vitro follicle growth •• Schmidt et al33 • 34 on the surplus medulla tissue that contains growing follicles and follicle activation •• Meirow et al •• Yin et al35 that do not sustain freezing (Table 3). Normally this tissue is •• Kristensen et al36 discharged, but we have ethical permission to ask women for •• Kristensen et al37 •• Rosendahl et al38 donation of this surplus tissue for research purposes. • Evaluation of potential malignant cell •• Rosendahl et al39 Furthermore, we can ask women who have cortical stored and 10 contamination in •• Andersen et al who do not wish to continue storage for permission to use the ovarian tissue •• Greve et al40 •• Greve et al40 tissue for research purposes. This has resulted in an unprece- •• Dolmans et al41 dented access to normal ovarian tissue both fresh and frozen •• Ernst et al42 43 from women at various ages and has allowed us to study human •• Sørensen et al •• Andersen et al44 folliculogenesis. •• El Issaoui et al45 Lately, we are focussing on establishing an optimised plat- •• Wilken-Jensen et al46 • In vitro maturation form for human in vitro maturation (IVM), since the surplus •• Yin et al47 •• Gruhn et al48 medulla tissue contains immature oocytes which may become a Transplant tissue to •• Schmidt et al49 surplus fertility-preservation option in case metaphase II (MII) • 50 restore reproductive •• Schmidt et al oocytes can be generated in sufficient numbers with sufficient and/or endocrine •• Rosendahl et al16 function •• Andersen et al51 quality. We are in the situation that IVM is not considered a •• Ernst et al42 standard procedure in Denmark, and we are legally unable to •• Greve et al52 use the MII oocytes generated for clinical purposes.47 •• Schmidt et al53 •• Greve et al54 •• Ernst et al55 •• Rosendahl et al56 Key points for success of the network •• Macklon et al57 •• Jensen et al11 The most important task of the network has been to establish •• Jensen et al58 a patient friendly and patient-oriented treatment offer that •• Jensen et al59 •• Gellert et al60 provided stable, reliable, and well-documented results in terms •• Matthwes et al61 of follicle survival in connection with the freezing procedure •• Lunding et al62 and renewed and improved ovarian function after transplanta- Cryopreservation and •• Schmidt et al15 • 8 tion. Our service has provided these results to a large extent: transport protocols do •• Rosendahl et al not affect tissue quality •• Kristensen et al63 nor follicle growth 1. Following transplantation frozen/thawed ovarian tissue •• Kristensen et al64 • Human preantral more than a total of 130 times; the tissue has consist- follicles •• Markholt et al65 66 ently provided renewed and improved ovarian function •• Kristensen et al •• Kristensen et al67 for variable time periods mainly depending on the initial •• Schmidt et al68 • Patient attitudes and follicular density, patient age, and amount of tissue effect of cryopreserv- •• Macklon et al69 transplanted. Except for one case, where a woman in her ing one ovary Wolff et al 7

mid-thirties had only three pieces of cortical tissue fro- a leadership team for 2 years each, in which both physicians zen, which did not result in ovarian function after (representatives of university and non-university centres) and transplantation. biologists were represented.73 Since 2008, private centres can 2. It has been a focus area to employ a freezing technique also become members. The network now also includes centres with as good a follicular survival rate as possible. We from Austria and Switzerland (www.fertiprotekt.de, www.fer- have recently published a new quantitative method to tiprotekt.ch, www.fertiprotekt.at, and www.fertiprotekt.com). evaluate follicular survival following a period of freezing However, the increasingly well-known national and inter- and found a survival rate of on average 84%, with a 91% national network was initially not a founded scientific society rate of healthy follicles in unfrozen control samples.70 and was in danger of, for example, being insufficiently recog- Furthermore, survival rates were constant over a period nised and acknowledged in professional policy discussions or in of freezing lasting 17 years and similar irrespective of the development of guidelines by other (including interdisci- whether the tissue was transported or not. plinary) scientific societies. Therefore, in 2015, the decision 3. During several different interviews, patients have was made to create a scientific society. The FertiPROTEKT expressed great satisfaction with the treatment offer and Network e.V. was founded by the then management team on the ability to stay in the local environment at difficult November 10, 2015, in Hamburg. The main office is in times having just faced a cancer diagnosis. The psycho- Germany (Marburg/Lahn). logical impact of having tissue stored has a massive posi- Centres that would like to become members of the tive impact on many patients. FertiPROTEKT network must prove with their application that they not only advise on fertility protection but that they can also implement all fertility-protective methods themselves What can be further improved and further challenges or in established cooperations. We have now recently documented that the quantitative sur- Structure vival of follicles during the freezing process is very high show- ing that only a minor part of follicles is lost during the freezing The FertiPROTEKT network comprises 125 centres. In 2017, process.70 In contrast, the follicle loss during transplantation 1156 consultations and 848 documented fertility-protective due to poor vascularization, ischemia, and reduced oxygen ten- therapies were performed (Figures 4 and 5). sion accounts for the clear majority of follicle demise. We are The structural characteristics shown in Table 1 are repre- therefore now trying to improve follicle survival during the ini- sented as follows in the network FertiPROTEKT. tial stages of revascularization by interfering with the processes Centralisation of facilities. that lead to follicle atresia. This applies to the centralization of Furthermore, one aspect that can be optimised and which is cryobanks for ovarian tissue in the FertiPROTEKT network. of obvious importance for the patients is the speed at which Specialised cryobanks are associated with the university gynae- cology clinics in Bonn, Düsseldorf, and Erlangen. There is no fertility preservation is executed. They may suffer a potential compulsory requirement for the member centres to send their deadly disease and require in many instances gonadotoxic samples to these cryobanks; however, they do so with great treatment as fast as possible. We are now trying to monitor the participation. speed at which the procedure is executed and whether there The cryobanks have established a transport logistics system may be cases where we can reduce the time needed to perform which plans that the peripheral member centre providing the fertility-preservation procedure. advice and the indication for cryopreservation of ovarian tissue orders a special transport container from the cryobank and has Introduction of FertiPROTEKT Network – a Partly it transported to the relevant centre. The latter sends the tissue Decentralised Network for Large Countries immediately postoperatively in this container in a nutrient History medium on ice (ie under defined conditions) to the cryobank At the start of this millennium, various scientific endeavours in overnight, where it is prepared and cryopreserved. the field of fertility protection already existed in Germany,71,72 Continuing education. From 2006 to 2018, 2-day working but there was still no coordinated counselling and care of meetings were held annually at different locations, organised patients. Therefore, at the initiative and invitation of Prof M. logistically and in terms of content by the board of the net- von Wolff (then Department of Gynaecological Endocrinology work and a representative of the member centre of each venue. and Fertility Disorders, Heidelberg) and Prof M. Montag In addition to individual lectures, the programme included (then Department of Gynaecological Endocrinology and workshops on various fertility-protection methods. From Reproductive Medicine, Bonn), 30 university reproductive 2018, these meetings will only be held every 2 years because medical centres met in Heidelberg in May 2006 and founded FertiPROTEKT has since then been able to conduct scientific the FertiPROTEKT network. The members elected meetings on topics of its own choice at least once a year at 8 Clinical Medicine Insights: Reproductive Health

Figure 4. FertiPROTEKT centres in Germany, Austria, and Switzerland.

their congress(es), thanks to its cooperation with other scien- adapted its data collection and evaluation for this purpose. The tific societies. FertiPROTEKT data will then be integrated into the so-called IVF Yearbook, in which the German IVF Register has pre- Data collection in registers. Data are currently entered in a self- sented the results of all German ART cycles for many years. created register, which is accessible to the member centres via FertiPROTEKT finances this cooperation including program- the intranet of the FertiPROTEKT homepage. These data are ming work and so on via the Society’s account. evaluated once a year and is presented to the members. From 2019, FertiPROTEKT will cooperate with the German IVF Political activities. FertiPROTEKT is a well-known and well- Register (https://www.deutsches-ivf-register.de/), which has networked contact partner for other scientific societies; patient Wolff et al 9

Figure 5. Number of documented counsellings and treatments performed by the large German-Austrian-Swiss network FertiPROTEKT. organisations including self-help groups or political parties fertility-protection measures even at short notice, who can also due to its long-standing presence at congresses; many publica- implement them promptly if they so wish. tions; and other scientific activities. The most important current focus of political activities is efforts to enforce the •• Coordination of content of counselling and therapies financing of fertility-protective services by the health insurance companies. Through studies, publications of recommendations and joint exchange among member centres and other specialist Financial support areas, the network has created a basis for the content-related consultation and implementation of fertility-protection thera- When the FertiPROTEKT network was founded, only a few pies. The annual 2-day national member meetings, in which thousand Euros were available from a pharmaceutical company approximately 200 persons participate, are an essential element to set up a website. All other costs were covered by the mem- for the coordination of content. bers. Annual continuing education was covered by pharmaceutical companies and participation fees. All other activities were •• Documentation of consultations and therapies in a register carried out on a voluntary basis. Since the founding of the FertiPROTEKT Society, mem- A register for fertility-protective consultations and therapies bership fees have been available which are charged annually per has existed since 2007. Due to the high quantity of data and the centre at a cost of 180 Euro. In addition, there are sponsoring further improvement in quality in the future (through data entry members in the form of pharmaceutical companies who via the national IVF register), there have been and will be oppor- together pay 15 000 Euro annually. These revenues can be used tunities in the future to clarify scientific questions. In addition, to run an office and fund board meetings as well as a few net- the amount of data is an argumentation aid, for example, in the work activities. The website and the register will continue to be enforcement of cost absorption by health insurance funds. run by the members on a voluntary basis. •• Initiation, implementation, and support of studies Scientific focus The scientific strengths lie in register analyses, studies with tis- The close cooperation and common interests in the network sue stored in centralised cryobanks, smaller multicentre studies, enable a timely agreement on the initiation of studies and their and the compilation of practically oriented recommendations implementation. Scientific questions from member centres can (Table 4). be dealt with conceptually within a short period of time and can be investigated by joint prospective or retrospective studies on larger amounts of data. Key points for success of the network •• Establishment of numerous and qualified counselling •• Definition of standards and publication of and therapy centres recommendations

The greatest merit of the network is the consolidation and Joint working meetings in combination with our own study coordination of many advisory member centres, which helps data and international experience form the basis for the con- patients and oncologists, to find a contact person for advice on stantly developing standards discussed in the network, as well 10 Clinical Medicine Insights: Reproductive Health

Table 4. Scientific focus and examples of corresponding publications with the participation of the FertiPROTEKT network.

Scientific focus Examples of publications*

•• von Wolff et al74 • Efficacy of luteal phase and random-start ovarian stimulation •• von Wolff et al75

•• Henes et al76 • Effectiveness of ovarian stimulation with various concurrent diseases •• Henes et al77 •• Henes et al78 •• von Wolff et al79

•• Dittrich et al80 • Transport and transplantation of ovarian tissue •• Dittrich et al81 •• Van der Ven et al2 •• Liebenthron et al82 •• von Wolff et al83

•• Huober-Zeeb et al84 • Combination of ovarian tissue cryopreservation and ovarian stimulation •• Sänger et al85 • Fertility protection in children and adolescents •• Sänger et al86

•• Lawrenz et al87 • Counselling and treatments in the network •• von Wolff et al88 •• von Wolff et al89

•• von Wolff et al90 • Recommendations for fertility protection •• Schüring et al91 •• von Wolff et al92 •• Dittrich et al93

*See also keyword «Fertiprotekt» in PubMed (www.ncbi.nlm.nih.gov). as published recommendations for counselling and therapy in reimbursement of fertility-protective measures by health the context of fertility protection. The first recommendations insurance companies. were published in 2011 with ‘online access’ to make them available to as many readers as possible free of charge.90 The update Introduction of the Oncofertility Consortium – A was carried out in 2018 with a paper on indications based on Decentralised Global Network selected diseases and another on fertility-protective tech- History niques.91,92 The association also financed the online access for these two publications. A German Austrian and Swiss guide- Oncofertility is a discipline that merges oncology with fertility line on fertility preservation was prepared and published93 by and has moved rapidly from the purview of individual champi- the AWMF with the contribution of FertiPROTEKT. ons to an integrated field that has become standard of care in 94 Furthermore, a practically orientated textbook on fertility pres- many institutions. Oncofertility as a field has developed in ervation has been published by the FertiPROTEKT network. parallel to the many life-preserving advances in oncologic care, It is currently re-edited and will then not only be available in including earlier diagnostics and the emergence of targeted English but also in German. cancer therapies, methods to reduce radiation dose and field, and localised surgical procedures. Addressing the complex treatment plans, general health, and quality of life issues that What can be further improved and further concern young cancer patients whose fertility may be threat- challenges ened by their disease or its treatment is a priority, and the At a strategy meeting in April 2018, the executive board of the Oncofertility Consortium has led efforts in this area for almost FertiPROTEKT network intensively discussed topics includ- 15 years.94-104 Northwestern University was first funded as a ing cost absorption by health insurance funds, research, mar- Specialised Cooperative Centre Programme in Reproductive keting, contacts with national, and international scientific Research (SCCPIR) in 2003, and the Centre for Reproductive societies as well as the documentation of register data and Research focused on understanding structure-function rela- developed a basis for concepts and solutions that will be tionships in reproductive science. This centre provided a mech- implemented over the coming years. The main objectives are, anism to bring new perspectives to reproductive science from on one hand, an even closer oncological link, for example, to ancillary disciplines (eg bioengineering and structure biology). oncological societies, to better coordinate the indications for In 2007, we transitioned this fundamental science to a National counselling, and for the implementation of fertility-protective Institutes of Health (NIH) Roadmap Interdisciplinary measures and, on the other hand, the implementation of cost Research Consortium – the Oncofertility Consortium – to Wolff et al 11 specifically address the intractable problem of fertility-preser- clinical case studies to facilitate a rapid pace of growth within vation options for young female cancer patients.94 In 2012, we the field and expand resources to non-malignant conditions. broadened the scope of the Oncofertility Consortium to The Oncofertility Conference is a place where the field-wide include the Centre for Reproductive Health After Disease, advances are shared through traditional lectures, hands-on whose mission is to protect and preserve the reproductive training, and small group sessions. The variety of education health – including fertility, endocrine health, sexuality, or the settings address the wide range of education levels and back- ability to carry an offspring to term – of women at reproductive grounds represented at the conference. risk after disease or treatment of disease. Fellow Education Day Symposium Structure At the annual Oncofertility Conference, we host an annual The multidisciplinary, international approach to the Fellow Education Day Symposium. The purpose of the course Oncofertility Consortium consists of research sites Oncofertility is to educate fellows on fertility-preservation options and sur- Professional Engagement Network (OPEN) Members, and vivorship care for cancer patients across the reproductive life key members of the multidisciplinary oncofertility team. The cycle. The course will also model a team approach to fertility- Oncofertility Consortium includes stakeholders across the preservation care. The course is comprised of didactic lectures width and depth of the academy, across departments and insti- given by leaders in the field interspersed with complex clinical tutions, and includes expert core facilities and sophisticated cases that will be reviewed in interdisciplinary teams. human specimen collection and use and disseminates our work Participants are supplementary materials for review before to patients, families, and the public. These are meaningful course attendance to facilitate an interactive ‘flipped classroom’ interactions that are fostered by the presence of a strong organ- approach to team-based learning. This course uses e-learning isation like the Oncofertility Consortium and through leader- modules that were created with the American Society for ship at the academic and staff level. Reproductive Medicine (ASRM).105

Centralisation of facilities. The Oncofertility Consortium Net- Oncofertility textbooks work spans six continents, including 40 countries around the globe and 97 sites in the United States (Figure 6). The OPEN Together with other colleagues in the field, we have published works to engage researchers and clinicians both domestically seven books to encompass the areas of basic science, ethics reli- and aboard, and these communities converge at the Annual gion and the law, medical practice, communication strategies, Oncofertility Consortium Conference held in Chicago, Illi- paediatric and disorders of sexual development populations, nois, each year. and non-oncologic and other non-malignant fertility threaten- ing conditions, as well as the first of its kind Oncofertility Continuing education. Education is a hallmark of the Oncofer- Textbook, which includes didactics. The hope is these books, tility Consortium’s programming. We have created numerous field forming and changing tools that have catalysed the growth which aggregate everything we know in the field, serve as a of oncofertility. These items include the first comprehensive starting point for material that will become integrated into the oncofertility textbook, training videos, and educational materi- major oncology, internal medicine, and reproductive texts of als that are enduring but also updatable. These products are our professions. listed below in more detail. In addition to these, we also house institutional review board (IRB) documents that can be used as templates for those wanting to start an oncofertility pro- Oncofertility Saturday Academy gramme, a Follicle Culture Handbook for basic scientists, and The Oncofertility Science Academy was created in 2007 as a many other materials that enable faster adoption of best prac- way to introduce underserved high school girls from the tices by members of the broader field. Through the use of Face- Chicagoland area to science and medicine by engaging them in book, Twitter, and other social media modalities, the hands-on lab and clinical activities on the Northwestern Oncofertility Consortium facilitates the ability of our projects University medical campus. Northwestern’s OSA programme to be communicated in a way that enables the public to see how impacted more than 275 students with 5 students securing the work is progressing in a lay-friendly manner. oncofertility research internships or employment within the Woodruff Lab; a true example of training the next generation of Annual Oncofertility Consortium Conference future clinicians and scientists. The Oncofertility Saturday The Oncofertility Consortium hosts an annual conference to Academy (OSA) model addresses the gap in reproductive sci- convene the field and set priorities for the upcoming year. ence education at the high school level and provides an adaptable Oncofertility Consortium focuses on providing attendees at education model that can be implemented across multiple insti- the annual Oncofertility Conference the ability to connect tutions. Currently, OSA curricula are available at Northwestern with colleagues from around the world to share research and University; University of Pennsylvania; University of California, 12 Clinical Medicine Insights: Reproductive Health

Figure 6. Decentralised structure of the Oncofertility Consortium. Purple indicates key research centres and green circles indicate OPEN members, both clinical and research sites around the globe.

San Diego; and Oregon National Primate Research Centre and Reproductive Health After Disease (P50HD076188) from the has impacted 545 high school girls nationally. Learning goals of NIH National Centre for Translational Research in OSA include providing students with hands-on laboratory and Reproduction and Infertility (NCTRI). The annual clinical activities, incorporating art modules for learning scien- Oncofertility Consortium Conference has been funded for tific and medical information in a new format and developing years by an NIH grant (5R13HD063248), as well as institu- relationships with scientists, doctors, and other professionals.106 tional funds from the Robert H. Lurie Comprehensive Cancer Centre at Northwestern University and the Office of the Data collection in registers President. In addition to these funds, we have secured other funding from industry partners including EMD Serono, The Oncofertility Consortium does not have any formal regis- Merck, Ferring, Walgreens, and Reprotech Ltd. We have tar- tries or patient data collection. geted a variety of sources to enable our success and made inno- vation and invention in communication methods a main Political activities mission of our programme. As the Oncofertility Consortium is housed within Northwestern University, the university policy limits lobbing activities and the Scientific focus Consortium’s ability to directly contact politicians and partici- •• Mechanisms underlying the fertility threat of life-pre- pate in many political activities. However, the Oncofertility serving cancer drugs (Figure 7, Table 5). Consortium works with other politically motivated groups, like •• Methods for cryopreservation (freezing), storing, and the Alliance for Fertility Preservation, to push forward legisla- growing ovarian and gonadal tissue. tive activities in any capacity within its scope. The Oncofertility •• In vitro follicle grown and oocyte maturation using a Consortium is the great convener in the United States and three-dimensional environment. helps to make critical connections among members of the •• Communication barriers between cancer patients and oncofertility community, like lawyers, patients, and politicians, health care providers. to ensure that fertility-preservation coverage is attainable in •• Ethical and legal concerns regarding the use of fertility- each state. Currently, there are five states in the United States preservation technologies in cancer patients. that require insurance companies to cover oncofertility and fertility-preservation services for cancer patients. Key points for success of the network Because of the intrinsic value in creating diverse networks and Financial support collaborations, the Oncofertility Consortium continues its Most of the funding for the Oncofertility Consortium’s activi- efforts to connect local centres of excellence and create a strong ties comes from the NIH and the Eunice Kennedy Shriver global network of diverse collaborators, many of whom may not Institute for Child Health and Human Development (NIH/ have worked together otherwise. The Oncofertility Consortium NICHD). Its efforts are currently supported by the Centre for supports interaction between global and local partners to create Wolff et al 13

Figure 7. 10 years of transforming traditional bench science in the Oncofertility Consortium network.

Table 5. Scientific focus and examples of corresponding publications with the participation of the Oncofertility Consortium network.

Scientific focus Examples of publications

•• Jakus et al107 • New technologies for fertility preservation and restoration •• Laronda et al108 •• Laronda et al109 •• Que et al110 •• Rios et al111 •• Skory et al112 •• Treff et al113

•• Silva et al114 • In vitro follicle growth •• Xiao et al115 •• Xiao et al116

•• Kidder117 • In vitro maturation •• Sowińska et al118

•• Lunardi et al119 • Transplant tissue to restore reproductive and/or endocrine function •• Oktay and Buyuk120 •• Salama and Woodruff121 •• Smith et al122

•• Kizuka-Shibuya et al123 • Create an embryo from mature follicles within the tissue •• Armstrong et al124 • Cryopreservation and transport protocols do not affect tissue quality nor follicle growth •• Duncan et al125 •• Duncan et al126

•• Duncan et al126 • Individual follicles can be cryopreserved and quality assessed •• Bortoletto et al127 • Primary follicle number may not be a predictor of future fertility and can be cultured •• Duncan et al125 •• Finlayson et al128 •• Kniazeva et al129 •• Laronda et al130 •• Tagler et al131

(Continued) 14 Clinical Medicine Insights: Reproductive Health

Table 5. (Continued)

Scientific focus Examples of publications

•• Duncan et al125 • Follicles can be grown in vitro to the large antral stage •• Ataman et al104 • Patient access •• Bortoletto et al127 •• Clayman et al132 •• Fuchs et al133 •• Gargus et al134 •• Lawson et al135 •• Lawson et al136 •• Llarena et al137 •• Rashedi et al138 •• Rashedi et al139 •• Stein et al140 •• Smith et al141 •• Waimey et al142 momentum for clinical activities (shared protocols and patient 4. McLaughlin M, Albertini DF, Wallace WHB, Anderson RA, Telfer EE. Meta- phase II oocytes from human unilaminar follicles grown in a multi-step culture case studies, inclusion of allied health professionals), research system. Mol Hum Reprod. 2018;24:135–142. (sharing results, both failures and successes, in ways that hasten 5. Picton HM, Wyns C, Anderson RA, et al. A European perspective on testicular tissue cryopreservation for fertility preservation in prepubertal and adolescent work), and meeting patient needs (educational websites, patient boys. Hum Reprod. 2015;30:2463–2475. decision tools, and patient navigator). By facilitating these inter- 6. Candy CJ, Wood MJ, Whittingham DG. Follicular development in cryopreserved marmoset ovarian tissue after transplantation. Hum Reprod. actions, the Oncofertility Consortium ensures the coordinated 1995;10:2334–2338. effort of the global oncofertility community in conducting cut- 7. Oktay K, Karlikaya G. Ovarian function after transplantation of frozen, banked ting-edge research that can continue to be rapidly translated to autologous ovarian tissue. N Engl J Med. 2000;342:1919. 8. Rosendahl M, Schmidt KT, Ernst E, et al. Cryopreservation of ovarian tissue for the clinic and establish an evidence-based standard of care. a decade in Denmark – an overview of the technique. Reprod Biomed Online. 2011;22:162–171. 9. Schmidt KL, Ernst E, Byskov AG, Andersen AN, Andersen CY. Survival of pri- What can be further improved and further mordial follicles following prolonged transportation of ovarian tissue prior to cryopreservation. Hum Reprod. 2003;18:2654–2659. challenges 10. Andersen CY, Kristensen SG, Greve T, Schmidt KT. Cryopreservation of ovarian tissue for fertility preservation in young female oncological patients. Future There are a number of common barriers that are commonly Oncol. 2012;8:595–608. identified by OPEN members and the Oncofertility Consortium. 11. Jensen AK, Kristensen SG, Macklon KT, et al. Outcomes of transplantations of cryopreserved ovarian tissue to 41 women in Denmark. Hum Reprod. These barriers include lack of insurance coverage and high out- 2015;30:2838–2845. of-pocket costs for patients, lack of awareness among providers 12. Kyono K, Hashimoto T, Toya M, et al. A transportation network for human and patients, cultural and religious constraints, and lack of fund- ovarian tissue is indispensable to success for fertility preservation. J Assist Reprod Genet. 2017;34:1469–1474. ing to help to support oncofertility programmes. Despite these 13. Andersen CY, Bollerup AC, Kristensen SG. Defining quality assurance and barriers, many opportunities exist to grow the field of oncofertil- quality control measures in connection with ovarian tissue cryopreservation and transplantation: a call to action. Hum Reprod. 2018;33:1201–1204. ity. Continuing to engage stakeholders around the globe and 14. Andersen CY, Byskov AG, Andersen AN. Cryopreservation of human ovarian expand the efforts of the Oncofertility Consortium will aid in tissue. Ugeskrift for Læger. 2001;163:5007–5013. 15. Schmidt KL, Byskov AG, Andersen AN, Muller J, Andersen CY. Density and the acceptance of oncofertility on a global level thus accelerating distribution of primordial follicles in single pieces of cortex from 21 patients and the pace of research from bench to bedside to babies. in individual pieces of cortex from three entire human ovaries. Hum Reprod. 2003;18:1158–1164. 16. Rosendahl M, Andersen CY, Ernst E, et al. Ovarian function after removal of an Author Contributions entire ovary for cryopreservation of pieces of cortex prior to gonadotoxic treat- MVW designed the manuscript. All authors prepared the ment: a follow up study. Hum Reprod. 2008;23:2475–2483. 17. Rosendahl M, Andersen CY, Freiesleben NC, Juul A, Løssl K, Andersen AN. manuscript and revised the final version. The dynamics of chemotherapy-induced ovarian follicular depletion in women of fertile age. Fertil Steril. 2010;94:156–166. 18. Schmidt KTL, Larsen EC, Andersen CY, Andersen AN. Risk of ovarian failure ORCID iD and fertility preserving methods in girls and adolescents with a malignant dis- Michael von Wolff https://orcid.org/0000-0003-4303-2734 ease. Brit J Obstet Gynaecol. 2010;117:163–174. 19. Andersen CY, Silber SJ, Berghold SH, Jorgensen JS, Ernst E. Long-term dura- tion of function of ovarian tissue transplants: case reports. Reprod Biomed Online. References 2012;25:128–132. 1. Donnez J, Dolmans MM, Demylle D, et al. Livebirth after orthotopic trans- 20. Donnez J, Dolmans MM, Pellicier A, et al. Fertility preservation for age related plantation of cryopreserved ovarian tissue. Lancet. 2004;364:1405–1410. fertility decline. Lancet. 2015;385:506–507. 2. Van der Ven H, Liebenthron J, Beckmann M, et al. Ninety-five orthotopic trans- 21. Andersen CY. Success and challenges in fertility preservation after ovarian tissue plantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility grafting. Lancet. 2015;385:1947–1948. preservation network: tissue activity, pregnancy and delivery rates. Hum Reprod. 22. Andersen CY, Kristensen SG. Novel use of the ovarian follicular pool to post- 2016;31:2031–2041. pone menopause and delay osteoporosis. Reprod Biomed Online. 2015;31: 3. Shirasawa H, Terada Y. In vitro maturation of human immature oocytes for 128–131. fertility preservation and research material. Reprod Med Biol. 2017;16: 23. Kristensen SG, Georgione V, Humaidan P, et al. Fertility preservation and re- 258–267. freezing of transplanted ovarian tissue – a potential new way of managing Wolff et al 15

patients with a low risk of malignant cell recurrence. Fertil Steril. cryopreservation of ovarian tissue for fertility preservation. Acta Obstet Gynecol 2017;107:1206–1213. Scand. 2014;93:32–37. 24. Kristensen SG, Liu Q , Mamsen LS, et al. A simple method to quantify follicle 47. Yin H, Kristensen SG, Jiang H, Andersen CY. Vitrification of in vitro matured survival in cryopreserved human ovarian tissue. Hum Reprod. oocytes collected from surplus ovarian medulla tissue resulting from fertility 2018;33:2276–2284. preservation of ovarian cortex tissue. J Assist Reprod Genet. 2016;33:741–746. 25. Andersen CY, Byskov AG. Is oestradiol an important regulator for secretion of 48. Gruhn JR, Kristensen SG, Andersen CY, Hoffmann ER. In vitro maturation anti-Mullerian hormone, inhibin-A and inhibin-B: analysis of fluid from small and culture of human oocytes. Methods Mol Biol. 2018;1818:23–30. antral and preovulatory human follicles. J Clin Endocrinol Metab. 49. Schmidt KLT, Andersen CY, Starup J, Loft A, Byskov AG, Andersen AN. 2006;91:4064–4069. Orthotopic autotransplantation of cryopreserved ovarian tissue to a woman 26. Andersen CY, Rosendahl M, Byskov AG. Concentration of anti-Mullerian hor- cured of cancer – follicular growth, steroid production and oocyte retrieval. mone and inhibin-B in relation to steroids and age in follicular fluid from small Reprod Biomed Online. 2004;8:448–453. antral human follicles. J Clin Endocrinol Metab. 2008;93:2344–2349. 50. Schmidt KLT, Andersen CY, Loft A, Byskov AG, Ernst E, Andersen AN. Fol- 27. Nielsen ME, Rasmussen IA, Fukuda M, Westergaard LG, Andersen CY. Con- low up of ovarian function post chemotherapy following ovarian cryopreserva- centrations of anti-Müllerian hormone in fluid from small human antral follicles tion and transplantation. Hum Reprod. 2005;20:3539–3546. shows a negative correlation with CYP19 mRNA expression in the correspond- 51. Andersen CY, Rosendahl M, Byskov AG, et al. Two successful pregnancies fol- ing granulosa cells. Mol Hum Reprod. 2010;16:637–643. lowing autotransplantation of frozen/thawed ovarian tissue. Hum Reprod. 28. Andersen CY, Schmidt KT, Kristensen SG, Rosendahl M, Byskov AG, Ernst E. 2008;23:2266–2272. Concentrations of AMH and inhibin-B in relation to follicular diameter in nor- 52. Greve T, Ernst E, Markholt S, Schmidt KT, Andersen CY. Legal termination of mal human small antral follicles. Hum Reprod. 2010;25:1282–1287. a pregnancy resulting from transplanted cryopreserved ovarian tissue. Acta Obstet 29. Nielsen ME, Rasmussen IA, Kristensen SG, et al. Expression of androgen- Gynecol Scand. 2010;89:1589–1591. receptor mRNA in granulosa cells from human small antral follicles and the cor- 53. Schmidt KT, Rosendahl M, Ernst E, et al. Autotransplantation of cryopreserved responding follicular fluid concentrations of androgens are positively correlated ovarian tissue in 12 women with chemotherapy-induced premature ovarian fail- to granulosa cell FSH receptor mRNA expression. Mol Hum Reprod. ure: the Danish experience. Fertil Steril. 2011;95:695–701. 2011;17:63–70. 54. Greve T, Clasen-Linde E, Andersen MT, et al. Cryopreserved ovarian cortex 30. Jeppesen JV, Nielsen ME, Kristensen SG, Andersen CY. Concentration of from patients with leukemia in complete remission contains no apparent viable activin A and follistatin in follicular fluid from human small antral follicles asso- malignant cells. Blood. 2012;120:4311–4316. ciated to gene expression of the corresponding granulosa cells. Mol Cell Endocri- 55. Ernst E, Kjærsgaard M, Birkebæk NH, Clausen N, Andersen CY. Stimulation nol. 2012;356:48–54. of puberty in a girl with chemo – and radiation therapy induced ovarian failure by 31. Jeppesen JV, Kristensen SG, Nielsen ME, et al. LH-receptor gene expression in transplantation of a small part of her frozen/thawed ovarian tissue. Eur J Cancer. human granulosa and cumulus cells from antral and preovulatory follicles. J Clin 2013;49:911–914. Endocrinol Metab. 2012;97:1524–1531. 56. Rosendahl M, Greve T, Andersen CY. The safety of transplanting cryopreserved 32. Jeppesen JV, Anderson RA, Kelsey TW, et al. Which follicles make the most ovarian tissue in cancer patients: a review of the literature. J Assist Reprod Genet. anti-Mullerian hormone in humans? evidence for an abrupt decline in AMH 2013;30:11–24. production at the time of follicle selection. Mol Hum Reprod. 2013;19: 57. Macklon KT, Jensen AK, Loft A, Ernst E, Andersen CY. Treatment history and 519–527. outcome of 24 deliveries worldwide after autotransplantation of cryopreserved 33. Schmidt KLT, Kryger-Baggesen N, Byskov AG, Andersen CY. Anti-Müllerian ovarian tissue, including two new Danish deliveries years after autotransplanta- hormone initiates growth of human primordial follicles in-vitro. Mol Cell Endo- tion. J Assist Reprod Genet. 2014;31:1557–1564. crinol. 2005;234:87–93. 58. Jensen AK, Rechnitzer C, Macklon KT, et al. Cryopreservation of ovarian tissue 34. Meirow D, Roness H, Kristensen SG, Andersen CY. Optimizing outcomes from for fertility preservation in a large cohort of young girls: focus on pubertal devel- ovarian tissue cryopreservation and transplantation; activation versus preserva- opment. Hum Reprod. 2017;32:154–164. tion. Hum Reprod. 2015;30:2453–2436. 59. Jensen AK, Macklon KT, Fedder J, et al. Erratum to: 86 successful births and 9 35. Yin H, Kristensen SG, Jiang H, Rasmussen A, Andersen CY. Survival and ongoing pregnancies worldwide in women transplanted with frozen-thawed growth of isolated pre-antral follicles from human ovarian medulla tissue during ovarian tissue: focus on birth and perinatal outcome in 40 of these children. J long-term three-dimensional culture. Hum Reprod. 2016;31:1531–1539. Assist Reprod Genet. 2017;34:337. 36. Kristensen SG, Pors SE, Andersen CY. Improving oocyte quality by transfer of 60. Gellert SE, Pors SE, Kristensen SG, et al. Transplantation of frozen-thawed autologous mitochondria from fully grown oocytes. Hum Reprod. ovarian tissue: an update on worldwide activity published in peer-reviewed 2017;32:725–732. papers and on the Danish cohort. J Assist Reprod Genet. 2018;35:561–570. 37. Kristensen SG, Pors SE, Andersen CY. Diving into the follicle pool. Curr Opin 61. Matthews SJ, Picton HM, Ernst E, Andersen CY. Successful pregnancy in a Obstet Gynecol. 2017;29:112–118. woman previously suffering from β-thalassaemia following transplantation of 38. Rosendahl M, Andersen MT, Ralfkjær E, et al. Evidence of residual disease in ovarian tissue cryopreserved before puberty. Minerva Ginecol. 2018;70:432–435. cryopreserved ovarian cortex from female patients with leukaemia. Fertil Steril. 62. Lunding SA, Pors SE, Kristensen SG, et al. Autotransplantation of fragmented ovarian 2010;94:2186–2190. cortical tissue: a laparoscopic demonstration. Fertil Steril. 2018;110:1181–1183. 39. Rosendahl M, Wielenga VT, Nedergaard L, et al. Cryopreservation of ovarian 63. Kristensen SG, Mamsen LS, Jeppesen JV, et al. Hallmarks of human small tissue for fertility preservation: no evidence of malignant cell contamination in antral follicle development: implications for regulation of ovarian steroidogenesis ovarian tissue from patients with breast cancer. Fertil Steril. and selection of the dominant follicle. Front Endocrinol (Lausanne). 2018;8:376. 2011;95:2158–2161. 64. Kristensen SG, Rasmussen A, Byskov AG, Andersen CY. Isolation of preantral 40. Greve T, Wielenga VT, Grauslund M, et al. Ovarian tissue cryopreserved for follicles from human ovarian medulla tissue. Hum Reprod. 2011;26:157–166. fertility preservation from patients with Ewing or other sarcomas appear to have 65. Markholt S, Grøndahl ML, Ernst EH, Andersen CY, Ernst E, Lykke-Hart- no tumor cell contamination. Eur J Cancer. 2013;49:1932–1938. mann K. Global gene analysis of oocytes from early stages in human folliculo- 41. Dolmans MM, Luyckx V, Donnez J, Andersen CY, Greve T. Risk of transfer- genesis shows high expression of novel genes in reproduction. Mol Hum Reprod. ring malignant cells with transplanted frozen-thawed ovarian tissue. Fertil Steril. 2012;18:96–110. 2013;99:1514–1522. 66. Kristensen SG, Andersen K, Clement AC, Andersen CY. Expression of TGF- 42. Ernst EH, Offersen BV, Andersen CY, Ernst E. Legal termination of a preg- beta superfamily growth factors, their receptors, and the associated SMADs in nancy resulting from transplanted cryopreserved ovarian tissue due to cancer five isolated size-matched populations of preantral follicles from normal human recurrence. J Assist Reprod Genet. 2013;30:975–978. ovaries. Mol Hum Reprod. 2014;20:293–308. 43. Sørensen SD, Greve T, Wielenga VT, Wallace WHB, Andersen CY. Safety consid- 67. Kristensen SG, Ebbesen P, Andersen CY. Transcriptional profiling of five iso- erations for transplanting frozen/thawed ovarian tissue to restore fertility in patients lated size-matched stages of human preantral follicles. Mol Cell Endocrinol. who have recovered from Ewing sarcoma. Future Oncol. 2014;10:277–283. 2015;401C:189–201. 44. Andersen CY, Ernst E, Bærentzen S, Birkebæk NH, Clausen N. No malignancy 68. Schmidt KTA, Andersen TN, Greve E, Ernst A, Loft A, Andersen CY. Fertility detected in surplus ovarian tissue from a former Ewing sarcoma patient who in cancer patients after cryopreservation of one ovary. Reprod Biomed Online. experienced relapse four years after being grafted with frozen/thawed ovarian 2013;26:272–279. tissue. J Assist Reprod Genet. 2014;31:1567–1568. 69. Macklon KT, Ernst E, Andersen AN, Andersen CY. Cryobanking of human 45. El Issaoui M, Giorgione V, Mamsen LS, et al. Effect of first line cancer treat- ovarian tissue: do women still want their tissue stored beyond 5 years? Reprod ment on the ovarian reserve and follicular density in girls under the age of 18 Biomed Online. 2014;29:452–456. years. Fertil Steril. 2016;106:1757–1762. 70. Kristensen SG, Andersen CY. Cryopreservation of ovarian tissue: opportunities 46. Wilken-Jensen H, Kristensen SG, Jeppesen JV, Andersen CY. Developmental beyond fertility preservation and a positive view into the future. Front Endocrinol competence of oocytes isolated from surplus medulla tissue in connection with (Lausanne). 2018;9:347. 16 Clinical Medicine Insights: Reproductive Health

71. Liebermann J, Nawroth F, Isachenko V, et al. Potential importance of vitrifica- 99. Woodruff TK. The Oncofertility Consortium – addressing fertility in young tion in reproductive medicine. Biol Reprod. 2002;67:1671–1680. people with cancer. Nat Rev Clin Oncol. 2010;7:466–475. 72. Isachenko V, Isachenko E, Rahimi G, et al. Cryopreservation of human ovarian 100. Woodruff TK. Reproductive endocrinology: fertility in female survivors of tissue by direct plunging into liquid nitrogen: negative effects of disaccharides in childhood cancer. Nat Rev Endocrinol. 2013;9:571–572. vitrification solution. CryoLetters. 2002;23:333–344. 101. Woodruff TK, Gosiengfiao YC. Pediatric and Adolescent Oncofertility: Best Prac- 73. Nawroth F, von Wolff M. FertiPROTEKT Netzwerk e.V. – das interdisziplinäre tices and Emerging Technologies. Cham, Switzerland: Springer; 2017. Netzwerk für fertilitätsprotektive Maßnahmen. Gynäkologe 2018;51:951–958. 102. Woodruff TK, Snyder KA. Oncofertility: Fertility Preservation for Cancer Survi- 74. von Wolff M, Thaler CJ, Frambach T, et al. Ovarian stimulation to cryopreserve vors. New York, NY: Springer; 2007. fertilized oocytes in cancer patients can be started in the luteal phase. Fertil 103. Woodruff TK. Oncofertility: Ethical, Legal, Social, and Medical Perspectives. New Steril. 2009;92:1360–1365. York, NY: Springer; 2010. 75. von Wolff M, Capp E, Jauckus J, et al. Timing of ovarian stimulation in patients 104. Ataman LM, Rodrigues JK, Marinho RM, et al. Creating a global community prior to gonadotoxic therapy: an analysis of 684 stimulations. Eur J Obstet Gynecol of practice for oncofertility. J Glob Oncol. 2016;2:83–96. Reprod Biol. 2016;199:146–149. 105. Miller EJN, Cookingham LM, Woodruff TK, et al. Fertility preservation train- 76. Henes M, Henes JC, Neunhoeffer E, et al. Fertility preservation methods in ing for obstetrics and gynecology fellows: a highly desired but non-standardized young women with systemic lupus erythematosus prior to cytotoxic therapy: experience. Fertil Res Pract. 2017;3:9. experiences from the FertiPROTEKT network. Lupus. 2012;21:953–958. 106. Castle M, Cleveland C, Gordon D, et al. Reproductive science for high school stu- 77. Henes JC, Henes M, von Wolff M, et al. Fertility preservation in women with dents: a shared curriculum model to enhance student success. Biol Reprod. 2016;95:28. vasculitis: experiences from the FertiPROTEKT network. Clin Exp Rheumatol. 107. Jakus AE, Laronda MM, Rashedi AS, et al. ‘Tissue papers’ from organ-specific 2012;30:S53–S56. decellularized extracellular matrices. Adv Funct Mater. 2017;27:1700992. 78. Henes M, Neis F, Krämer B, et al. Possibilities of fertility preservation in young 108. Laronda MM, Jakus AE, Whelan KA, Wertheim JA, Shah RN, Woodruff TK. patients with ovarian cancer. Anticancer Res. 2014;34:3851–3854. Initiation of puberty in mice following decellularized ovary transplant. Biomate- 79. von Wolff M, Bruckner T, Strowitzki T, Germeyer A. Fertility preservation – rials. 2015;50:20–29. ovarian response to freeze oocytes is not affected by different malignant diseases 109. Laronda MM, McKinnon KE, Ting AY, Le Fever AV, Zelinski MB, Woodruff – an analysis of 992 stimulations. J Assist Reprod Genet. 2018;35:1713–1719. TK. Good manufacturing practice requirements for the production of tissue vit- 80. Dittrich R, Lotz L, Keck G, et al. Live birth after ovarian tissue autotransplan- rification and warming and recovery kits for clinical research. J Assist Reprod tation following overnight transportation before cryopreservation. Fertil Steril. Genet. 2017;34:291–300. 2012;97:387–390. 110. Que EL, Bleher R, Duncan FE, et al. Quantitative mapping of zinc fluxes in the 81. Dittrich R, Hackl J, Lotz L, Hoffmann I, Beckmann MW. Pregnancies and live mammalian egg reveals the origin of fertilization-induced zinc sparks. Nat births after 20 transplantations of cryopreserved ovarian tissue in a single center. Chem. 2015;7:130–139. Fertil Steril. 2015;103:462–468. 111. Rios PD, Kniazeva E, Lee HC, et al. Retrievable hydrogels for ovarian 82. Liebenthron J, Montag M, Reinsberg J, et al. Overnight ovarian tissue transpor- follicle transplantation and oocyte collection. Biotechnol Bioeng. 2018;115: tation for centralized cryobanking – a feasible option [published online ahead of 2075–2086. print January 19, 2019]. Reprod Biomed Online. doi:10.1016/j.rbmo.2019.01.006. 112. Skory RM, Xu Y, Shea LD, Woodruff TK. Engineering the ovarian cycle using 83. von Wolff M, Sänger N, Liebenthron J. Is ovarian tissue cryopreservation and trans- in vitro follicle culture. Hum Reprod. 2015;30:1386–1395. plantation still experimental? it is a matter of female age and type of cancer [published 113. Treff NR, Krisher RL, Tao X, et al. Next generation sequencing-based compre- online ahead of print October 5, 2018]. J Clin Oncol. doi:10.1200/JCO.18.00425. hensive chromosome screening in mouse polar bodies, oocytes, and embryos. 84. Huober-Zeeb C, Lawrenz B, Popovici RM, et al. Improving fertility preserva- Biol Reprod. 2016;94:76. tion in cancer: ovarian tissue cryobanking followed by ovarian stimulation can be 114. Silva GM, Rossetto R, Chaves RN, et al. In vitro development of secondary fol- efficiently combined. Fertil Steril. 2011;95:342–344. licles from pre-pubertal and adult goats cultured in two-dimensional or three- 85. Sänger N, Jarisch A, Ochsendorf F, et al. Fertility preservation in prepubertal dimensional systems. Zygote. 2015;23:475–484. and pubertal children and adolescents. Klin Padiatr. 2018;230:122–129. 115. Xiao S, Duncan FE, Bai L, Nguyen CT, Shea LD, Woodruff TK. Size-specific 86. Sänger N, Jarisch A, von Wolff M. Pädiatrische Onkologie: Fertilitätserhalt bei follicle selection improves mouse oocyte reproductive outcomes. Reproduction. Kindern mit Krebs. Dtsch Arztebl. 2018;115:A-196, B-172, C-172. 2015;150:183–192. 87. Lawrenz B, Jauckus J, Kupka MS, Strowitzki T, von Wolff M. Fertility preserva- 116. Xiao S, Zhang J, Romero MM, et al. In vitro follicle growth supports human tion in >1,000 patients: patient’s characteristics, spectrum, efficacy and risks of oocyte meiotic maturation. Sci Rep. 2015;5:17323. applied preservation techniques. Arch Gynecol Obstet. 2011;283:651–656. 117. Kidder BL. In vitro maturation and in vitro fertilization of mouse oocytes and 88. von Wolff M, Dittrich R, Liebenthron J, et al. Fertility-preservation counselling preimplantation embryo culture. Methods Mol Biol. 2014;1150:191–199. and treatment for medical reasons: data from a multinational network of over 118. Sowińska N, Frankowska K, Filipczyk A, et al. The effect of cumulus cells on 5000 women. Reprod Biomed Online. 2015;31:605–612. domestic cat (Felis catus) oocytes during in vitro maturation and fertilization. 89. von Wolff M, Giesecke D, Germeyer A, et al. Characteristics and attitudes of Reprod Domest Anim. 2017;52:108–113. women in relation to chosen fertility preservation techniques: a prospective, mul- 119. Lunardi FO, Araújo VR, Bernuci MP, et al. Restoring fertility after ovarian ticenter questionnaire-based study with 144 participants. Eur J Obstet Gynecol tissue cryopreservation: a half century of research. Zygote. 2013;21:394–405. Reprod Biol. 2016;201:12–17. 120. Oktay K, Buyuk E. The potential of ovarian tissue transplant to preserve fertility. 90. von Wolff M, Montag M, Dittrich R, et al. Fertility preservation in women – a Expert Opin Biol Ther. 2002;2:361–370. practical guide to preservation techniques and therapeutic strategies in breast 121. Salama M, Woodruff TK. New advances in ovarian autotransplantation to cancer, Hodgkin’s lymphoma and borderline ovarian tumours by the fertility restore fertility in cancer patients. Cancer Metastasis Rev. 2015;34:807–822. preservation network FertiPROTEKT. Arch Gynecol Obstet. 2011;284:427–435. 122. Smith RM, Shikanov A, Kniazeva E, Ramadurai D, Woodruff TK, Shea LD. 91. Schüring AN, Fehm T, Behringer K, et al. Practical recommendations for fertil- Fibrin-mediated delivery of an ovarian follicle pool in a mouse model of infertility preservation in women by the FertiPROTEKT network. Part I: indications ity. Tissue Eng Part A. 2014;20:3021–3030. for fertility preservation. Arch Gynecol Obstet. 2018;297:241–255. 123. Kizuka-Shibuya F, Tokuda N, Takagi K, et al. Locally existing endothelial cells 92. von Wolff M, Germeyer A, Liebenthron J, Korell M, Nawroth F. Practical recom- and pericytes in ovarian stroma, but not bone marrow-derived vascular progeni- mendations for fertility preservation in women by the FertiPROTEKT network. tor cells, play a central role in neovascularization during follicular development Part II: fertility preservation techniques. Arch Gynecol Obstet. 2018;297:257–267. in mice. J Ovarian Res. 2014;7:10. 93. Dittrich R, Kliesch S, Schüring A, et al. Fertility preservation for patients with 124. Armstrong AG, Kimler BF, Smith BM, Woodruff TK, Pavone ME, Duncan malignant disease. Guideline of the DGGG, DGU and DGRM (S2k–level, FE. Ovarian tissue cryopreservation in young females through the Oncofertility AWMF Registry No. 015/082, November 2017) – recommendations and state- Consortium’s National Physicians Cooperative. Future Oncol. 2018;14: ments for girls and women. Geburtshilfe Frauenheilkd. 2018;78:567–584. 363–378. 94. Woodruff TK. Oncofertility: a grand collaboration between reproductive medi- 125. Duncan FE, Pavone ME, Gunn AH, et al. Pediatric and teen ovarian tissue cine and oncology. Reproduction. 2015;150:S1–S10. removed for cryopreservation contains follicles irrespective of age, disease diag- 95. De Vos M, Smitz J, Woodruff TK. Fertility preservation in women with cancer. nosis, treatment history, and specimen processing methods. J Adolesc Young Adult Lancet. 2014;384:1302–1310. Oncol. 2015;4:174–183. 96. Gracia C. Oncofertility Medical Practice: Clinical Issues and Implementation (ed. 126. Duncan FE, Zelinski M, Gunn AH, et al. Ovarian tissue transport to expand Woodruff, TK). New York, NY: Springer; 2012. access to fertility preservation: from animals to clinical practice. Reproduction. 97. Woodruff TK. The emergence of a new interdiscipline: oncofertility. Cancer Treat 2016;152:R201–R210. Res. 2007;138:3–11. 127. Bortoletto P, Confino R, Smith BM, Woodruff TK, Pavone ME. Practices and 98. Woodruff TK. Preserving fertility during cancer treatment. Nat Med. attitudes regarding women undergoing fertility preservation: a survey of the 2009;15:1124–1125. National Physicians Cooperative. J Adolesc Young Adult Oncol. 2017;6:444–449. Wolff et al 17

128. Finlayson C, Fritsch MK, Johnson EK, et al. Presence of germ cells in disorders of 136. Lawson AK, Klock SC, Pavone ME, Hirshfeld-Cytron J, Smith KN, Kazer RR. sex development: implications for fertility potential and preservation. J Urol. Psychological counseling of female fertility preservation patients. J Psychosoc 2017;197:937–943. Oncol. 2015;33:333–353. 129. Kniazeva E, Hardy AN, Boukaidi SA, Woodruff TK, Jeruss JS, Shea LD. 137. Llarena NC, Estevez SL, Tucker SL, Jeruss JS. Impact of fertility concerns Primordial follicle transplantation within designer biomaterial grafts pro- on tamoxifen initiation and persistence. J Natl Cancer Inst. 2015;107: duce live births in a mouse infertility model. Sci Rep. 2015;35:17709. djv202. 130. Laronda MM, Duncan FE, Hornick JE, et al. Alginate encapsulation supports 138. Rashedi AS, de Roo SF, Ataman LM, et al. Survey of fertility preservation the growth and differentiation of human primordial follicles within ovarian cor- options available to patients with cancer around the globe. J Glob Oncol. 2018;4: tical tissue. J Assist Reprod Genet. 2014;31:1013–1028. 1–16. 131. Tagler D, Makanji Y, Tu T, et al. Promoting extracellular matrix remodeling via 139. Rashedi AS, de Roo SF, Ataman LM, et al. Survey of third-party parenting ascorbic acid enhances the survival of primary ovarian follicles encapsulated in options associated with fertility preservation available to patients with cancer alginate hydrogels. Biotechnol Bioeng. 2014;111:1417–1429. around the globe. J Glob Oncol. 2018;4:1–7. 132. Clayman ML, Harper MM, Quinn GP, Reinecke J, Shah S. Oncofertility 140. Stein DM, Victorson DE, Choy JT, et al. Fertility preservation preferences and resources at NCI-designated comprehensive cancer centers. J Natl Compr Canc perspectives among adult male survivors of pediatric cancer and their parents. J Netw. 2013;11:1504–1509. Adolesc Young Adult Oncol. 2014;3:75–82. 133. Fuchs A, Kashanian JA, Clayman ML, et al. Pediatric oncology providers’ atti- 141. Smith BM, Duncan FE, Ataman L, et al. The National Physicians Cooperative: tudes and practice patterns regarding fertility preservation in adolescent male transforming fertility management in the cancer setting and beyond. Future cancer patients. J Pediatr Hematol Oncol. 2016;38:118–122. Oncol. 2019;14:3059–3072. 134. Gargus E, Deans R, Anazodo A, Woodruff TK. Management of primary ovar- 142. Waimey KE, Smith BM, Confino R, Jeruss JS, Pavone ME. Understanding fer- ian insufficiency symptoms in survivors of childhood and adolescent cancer. J tility in young female cancer patients. J Womens Health (Larchmt). 2015;24: Natl Compr Canc Netw. 2018;16:1137–1149. 812–818. 135. Lawson AK, Klock SC, Pavone ME, Hirshfeld-Cytron J, Smith KN, Kazer RR. 143. Greve T, Schmidt KT, Kristensen SG, Ernst E, Andersen CY. Evaluation of the Prospective study of depression and anxiety in female fertility preservation and ovarian reserve in women transplanted with frozen and thawed ovarian cortical infertility patients. Fertil Steril. 2014;102:1377–1384. tissue. Fertil Steril. 2012;97:1394–1398.